POS0833 DIFFERENCES BETWEEN AVACOPAN AND PREDNISONE FOR THE TREATMENT OF ANCA-ASSOCIATED VASCULITIS AT DIFFERENT THRESHOLDS OF GLUCOCORTICOID TOXICITY
Authors: N. Patel, Y. Zhang, D. Jayne, P. A. Merkel, H. Yue, P. Bekker, J. H. Stone
Journal: Annals of the Rheumatic Diseases (2022)

Background Treatment with glucocorticoids (GCs) for ANCA-associated vasculitis (AAV) is associated with substantial toxicity. The Glucocorticoid Toxicity Index (GTI) was developed to measure change in GC toxicity over time. 1 Data from the composite GTI domains provide both an Aggregate Improvement Score (AIS) and a Cumulative Worsening Score (CWS) of GC toxicity, permitting the instrument to compare both improvement and worsening of GC toxicity across treatment groups. The GTI was a pre-specified secondary outcome in ADVOCATE, a randomized, double-blind, placebo-controlled trial in patients with AAV that aimed to replace a GC taper with avacopan, a complement C5a receptor inhibitor. Patients were randomized to either avacopan or a prednisone taper on a background of either cyclophosphamide or rituximab. 2 In ADVOCATE, the median GC exposure was 400 mg vs. 2939 mg in the avacopan and prednisone groups, respectively, which is an 86% median reduction in GC exposure from all sources. Remission rates were comparable in the two groups at 26 weeks (72.3% vs. 70.1%, respectively), and avacopan was superior at 52 weeks (sustained remission in 65.7% vs. 54.9%). 2 Objectives To compare GC toxicity between the treatment groups at three different thresholds of GC toxicity, beginning with the minimum detectable difference (MDD) of the GTI. Methods The MDD for the GTI (10 points) was calculated in the initial validation phase of the instrument. Thus, any GTI score &gt; 10 points may be considered to represent a true change in GC toxicity. We compared the two groups at GTI thresholds of 10, 20, and 30 points for both the CWS and AIS. The CWS comprises a total of all GC-related toxicities that have occurred in the GTI between baseline and 26 weeks (time of primary outcome). The AIS, in contrast, allows toxicities to be added if they are new or subtracted if they improve. Higher CWS and AIS values indicate greater severity of GC toxicity. The two scores together capture the nuances of longitudinal GC toxicity across multiple domains. We compared the percentages of those in the two treatment groups who exceeded GTI threshold values of 10, 20, and 30 points in the CWS or AIS. Results The percentages of patients exceeding the specified AIS thresholds differentiated the avacopan group from the prednisone group (48.2% vs. 60.4%, respectively, at the 10-point threshold, p=0.02; 29.5% vs. 45.1% at the 20-point threshold, p=0.003; and 18.1% vs. 33.5% at the 30-point threshold, p=0.001) (Table 1). The CWS differentiated avacopan from prednisone at the 20- and 30-point thresholds (57.8% vs 73.2%, respectively, at 20 points, p=0.002; 41.0% vs 55.5% at 30 points, p=0.007). Table 1. Percentages of Patients in ADVOCATE Exceeding Selected GTI Thresholds at Week 26 GTI threshold/study group n (%) exceeding CWS threshold p-value n (%) exceeding AIS threshold p-value GTI worsening &gt; 10 points Avacopan (N = 164) 138 (83.1%) 0.147 80 (48.2%) 0.022 Prednisone (N = 166) 144 (87.8%) 99 (60.4%) GTI worsening &gt; 20 points Avacopan (N = 164) 96 (57.8%) 0.002 49 (29.5%) 0.003 Prednisone (N = 166) 120 (73.2%) 74 (45.1%) GTI worsening &gt; 30 points Avacopan (N = 164) 68 (41.0%) 0.007 30 (18.1%) 0.001 Prednisone (N = 166) 91 (55.5%) 55 (33.5%) AIS, Aggregate Improvement Score; CWS, Cumulative Worsening Score; GTI, Glucocorticoid Toxicity Index Conclusion Among patients with AAV, treatment with avacopan was associated with lower GC toxicity across multiple GTI thresholds compared to treatment with prednisone, consistent with the substantial reduction in total GC exposure associated with avacopan. The GTI scores differentiated the two treatment groups effectively through a composite of GC toxicity domains. References [1]McDowell PJ, Stone JH, Zhang Y, et al. Quantification of Glucocorticoid-Associated Morbidity in Severe Asthma Using the Glucocorticoid Toxicity Index. J Allergy Clin Immunol Pract . 2021; 9:365-72. [2]Jayne DRW, Merkel PA, Schall TJ, et al. Avacopan for the Treatment of ANCA-Associated Vasculitis. N Engl J Med . 2021;384:599-609. Disclosure of Interests Naomi Patel: None declared, Yuqing Zhang: None declared, David Jayne Speakers bureau: Amgen, Vifor, Consultant of: Astra-Zeneca, BMS, Boehringer-Ingelheim, Chemocentryx, GSK, Novartis, Otsuka, Roche/Genentech, Takeda, UCB &amp; Vifor, Grant/research support from: GSK, Roche/Genentech, Peter A Merkel Consultant of: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, Immagene, InflaRx, Jannsen, Kiniksa, Kyverna, Magenta, MiroBio, Novartis, Pfizer, Regeneron, Sparrow, Takeda, Talaris, Grant/research support from: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Sanofi, Takeda, Huibin Yue Shareholder of: ChemoCentryx, Employee of: ChemoCentryx, Pirow Bekker Shareholder of: ChemoCentryx, Consultant of: ChemoCentryx, Employee of: ChemoCentryx, John H. Stone Shareholder of: Steritas, Consultant of: ChemoCentryx, Roche/Genentech, Sanofi, Bristol-Myers Squib, AbbVie, InflaRx, Kyverna, Novartis, Q32Bio, Zenas, Horizon, Grant/research support from: Roche/Genentech, Horizon, Sanofi, Bristol-Myers Squib